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For the legion of youngsters clamoring to have designer
jeans and other high-priced trendy items, there is also a smaller,
no less vocal group pushing on behalf of kids for other expensive,
but much more crucial, tailor-made products — designer drugs.
It's the growing trend toward individualized medicine — no
more evident than in research on childhood cancers — that
presents both promise and problems in efforts against the disease,
according to scientists at an Apr. 26 NCI/Children's Inn seminar.
"How do we get further?" asked Dr. Alan Wayne, clinical director of the Pediatric Oncology
Branch at NCI's Center for Cancer Research. "As with any big complex problem in our complex
society, we do it in a multifaceted, collaborative way. More and more it takes collaboration
from government, private industry, philanthropic organizations and regulatory bodies like the
FDA, as well as altruism, voices in the media and grassroots efforts — basically it takes
everybody working together with common goals."
Where We've Been
Many can remember the days when a diagnosis of childhood acute
lymphoblastic leukemia (ALL) was "a death sentence and survivals
were poor," Wayne recalled.
"In the 1960s to 70s, less than 5 percent
survived long term. Because of systematic improvements in therapy — and
particularly pediatric cooperative group trials here in North America — there
have been steady improvements such that now when children are diagnosed
with ALL they have an 80 — potentially 90 — percent chance
|Dr. Alan Wayne of NCI
Nonetheless, cancer is the number one cause of death from disease
in pediatrics, he said.
Approximately 1,600 cancer-related deaths occur each year in children
under age 21. Of the deaths from cancer, one third are the result
of leukemia, mainly ALL, which is the most common pediatric cancer
"Up until a few decades ago, leukemia was defined as a fatal disorder
of the blood-forming organs," stressed Dr. Donald Small of Johns
Hopkins University School of Medicine. "That is something that
has very much changed over time, thanks to improvements in therapy."
Small, the Kyle Haydock professor of oncology at JHU's Sidney
Kimmel Comprehensive Cancer Center, described several factors that
have boosted cure rates:
- Pediatric clinical trials — "Most of the drugs used to
fight childhood cancers have been around a long time," but the
progression of clinical studies in kids allowed doctors to discover
how best to combine the drugs.
- Combinations of chemotherapy — Doctors have learned to
use different drugs together to attack tumors.
- Treating spinal fluid, "which serves as a sanctuary where cancer
In addition, he explained, doctors can now better estimate patient
risk factors in order to change therapy, depending on how high
the child's relapse risk is. That was not possible even a decade
Wayne said bone marrow transplantation also has contributed to
better cancer-free survival. "Donor lymphocytes can eradicate cancer
cells without chemotherapy in an immunologic reaction referred
to as the 'allogeneic graft-versus-tumor effect,'" he explained.
Where We're Going
Researchers are now studying the biology of immune effectors
and targets of the immune reaction in order to develop therapies
using immune system cells as primary cancer treatments. Wayne said
his team is working on the first pediatric cancer clinical trial
of an allogeneic tumor vaccine.
|Dr. Donald Small of Johns Hopkins
describes several factors that have boosted cure rates.
||NCI Pediatric Oncology Branch chief
Dr. Lee Helman addresses moral and ethical concerns raised
by a burgeoning
era of designer therapy.
Another new approach uses information derived from genomic studies,
he continued. "What is clear not just in leukemia but in all cancers
is that the story lies in the biology of the disease," he explained. "Chromosome
and gene abnormalities inside leukemia cells influence the outlook
for a given individual. Genetic analysis now allows us to identify
children at greater risk of relapse who need more intensive therapy.
In addition, this technology can be used to point out potential
targets for therapeutics."
To illustrate the promise of targeted drugs and the importance
of pediatric clinical trials, Wayne told the story of Killian Owen,
a 9½ -year-old boy with ALL who became the first child to receive
BL22. [see sidebar below]
"Kids and families who work with us on these early developmental
trials absolutely know that the decks are stacked against them," Wayne
said. "However, they come to NIH with hope and a huge dose of altruism.
Yes, they are looking for magic bullets and we are trying to design
magic bullets. Ultimately when we come together here, most everybody
realizes that a miracle would be great for the individual child,
but the likely outcome will be a step forward in the very steady,
systematic progress in the war on pediatric cancer."
Steady progress, he pointed out, is based on rigorous scientific
work, which requires huge effort and resources. It also takes years
of intense teamwork. As examples, Wayne discussed several drugs
that target leukemia and are in the clinical trial pipeline for
- BL22, which Killian Owen was the first child to receive, was
developed at NCI and now with pharmaceutical partner Genencor.
Doctors have given the agent to more than a dozen children in
a phase I study at NCI.
- LMB2, a similar agent also designed by NCI to target a different
protein than BL22 found on the surface of certain cancer cells,
is also now under study in children.
- HA22, a newer generation agent related to BL22, is under development
jointly by NCI and Genencor.
Small predicted that similar tailored therapies are the near future
of cancer treatment. "Ultimately what will happen," he said, "is
people will come in with a tumor. We'll determine each individual's
mutations. [Then] we'll pull off the shelf a specific inhibitor for
a designer therapy."
Pioneers in Pediatric Cancer Drug Therapy
Owen Family Made Memories, History
Ten days before Christmas and just a couple of weeks before
the predicted Y2K D-day, a Georgia family of six experienced
a devastating event of its own: 5-year-old Killian Owen was
diagnosed with leukemia. In the 30 months ahead, Killian
would wage a fierce battle with the disease that accounts
for about 30 to 40 percent of childhood cancers.
|One legacy of Killian Owen is
the fundraiser his parents started to help other kids
By early 2003, after exhaustive treatments with several
rounds of chemotherapy and a bone marrow transplant procedure
(using marrow donated by fraternal twin brother Garrett),
Killian suffered yet another relapse.
"At that time we were told pretty much 'we could do nothing
[more],'" recalled dad Clay recently at the Children's Inn
at NIH. "We were told to go make some memories, so we did."
The Owens whisked their four sons off to Disney World to
shore up the good times. However, when they returned home,
mom Grainne refused to sit and wait for what they thought
was inevitable. She went to work searching the Internet for
answers. There had to be something, some experimental drug
or some final treatment option available to Killian. Sure
enough, she found a glimmer of hope in an online article
about a doctor at Emory University investigating what he
described as a targeted therapy.
Clay and Grainne Owen, discuss the tribute they began
in his memory.
"Traditional chemotherapy had failed," she explained. "Bone
marrow transplantation had failed. But, a drug called BL22
was designed for children with chemo-resistant leukemia,
which Killian had."
Within a week or so, her research led her and the entire
family to NIH and the inn.
"At that point, we really were hoping for the Hollywood
ending," Clay said.
Killian became the first child to receive BL22, a new drug
targeted to kill cells specific to his cancer.
"We were made very aware of all the risks," Grainne stressed,
choking with emotion. "But you see at that point he was dying
anyway. What did it matter if there were risks, because there
was no hope otherwise. The fact that Killian was given a
chance has led to so much hope for so many other children."
For several reasons, drug companies often hesitate to offer
new drugs for pediatric clinical trials, pointed out Dr.
Lee Helman, chief of the Pediatric Oncology Branch at NCI's
Center for Cancer Research.
"A lot of the drug companies are reluctant to move any of
these drugs into pediatric clinical trials," he said. "Pediatrics
is not a really big market and companies are worried that
adverse events that may occur in pediatric trials will ruin
chances for approval of the drug in adults."
That's why Killian's participation in the BL22 trial was
an important milestone in the fight against pediatric cancer.
"The Owen family played a pivotal role in releasing a logjam," explained
Dr. Alan Wayne, clinical director of Helman's branch. "Those
logjams are opening daily. The old paradigm — where
drugs have to go from mice to monkeys to adults to children — is
changing. The lessons [learned from treating Killian] are
clearly important. Those of us involved in the scientific
work feel more and more optimistic every day, based on translating
advances at the bench to movement forward in the clinic."
The Hollywood ending did not happen for the Owen family,
though. BL22 was not able to save Killian, who died at age
9½ in July 2003. However, hope for other children is what
brought mom and dad Owen back to the inn.
"There is a desperate lack of money in funding childhood
cancer research," Grainne explained. "You shouldn't have
to jump through the hoops that we had to jump through to
get your child to try a new drug. Two classrooms full of
children are being diagnosed [with cancer] every single day;
one in four of those children is going to die. That is an
amazing thought, that we're allowing that to happen. And
a lot of it is due to lack of funding."
The Owen family launched Coaches Curing Kids' Cancer, a
nationwide fundraiser that benefits CureSearch and the National
Childhood Cancer Foundation. Instead of buying little league
coaches a trinket or trophy at the end of a season, team
families pool their donations and send the amount to the
fundraiser to help further cancer research and its related
"We're going to get families in America behind this initiative," Grainne
declared. "We're going to raise awareness of childhood cancer.
We believe that it is possible to find cures to childhood
cancers in our lifetime. The technology, the science is there.
Killian's dream was to be a normal healthy child — a
very simple dream. Combine the power of science with the
power of the normal happy emotions that go with having normal
healthy children and help us find a cure for childhood cancer."
For more information on Killian's legacy and the charitable
foundation, visit Curingkidscancer.org.
However, such progress cannot occur without the help of brave
pioneers like the Owen family, who become partners with the research
community, said Wayne.
"Though the ultimate cure wasn't achieved for Killian," he remarked, "I
don't consider his case a failure. From a purely scientific standpoint,
we continue to use Killian's cancer cells and data to help us develop
a treatment that we hope will someday have a place in the curative
outcome for children like him in the future.
"Killian really does live on and continues to help us in many
ways," he concluded. "Families like the Owens highlight the highs
and lows of pediatric cancer therapy. Their experiences show us
where we've come from and where we need to go, which is critical.
We hope to get to the point where folks like the Owens only have
Detours Along the Way
Small also discussed another common childhood cancer, acute myeloblastic
leukemia (AML). The AML cure rate is only 40 percent. AML cells
are much more resistant to chemotherapy. He said researchers have
spent the last few decades defining changes that turn normally
growing cells into abnormally growing cells, or cancer. His group
cloned the human gene FLT3, which was later discovered by a team
in Japan to have a mutation that is instrumental in turning good
cells bad in some patients.
"[Expression of the FLT3 gene] takes a disease that is really,
really bad and makes it worse," Small explained. "These patients
have very little chance of cure."
Because of the FLT3 data, he continued, a number of research teams
have launched aggressive searches for FLT3 inhibitors. Several
agents already have been identified, including a drug called CEP-701
that Small's team is now ushering through various clinical trial
design and approval stages.
"Unfortunately chemotherapy is the best we have to deal with these
tumors, and we have gotten some really good cure rates with chemo
for certain types of tumors," Small said. "But really all they
are is poisons that kill rapidly proliferating cells, but also
kill normal cells that proliferate as well. In addition, because
these chemotherapies are non-specific, they can damage non-proliferating
cells as well, so you can get side effects that damage the brain,
heart and liver — just about any organ. [Scientists are now
focusing on] molecular targeted therapy, where you have small molecules
that kill only the cells that have the targeted protein in them
and will leave normal proliferating cells unaffected and should
have no effect on non-proliferating cells."
NCI Pediatric Oncology Branch chief Dr. Lee Helman, who studies
solid tumors in children, offered a sobering summary of the battle
against cancer that has spread.
"While progress has been good for non-metastatic disease," he
said, "little progress has been made for patients diagnosed with
widely spread cancer.For children who walk in our doors with disseminated
disease, we really haven't changed things in 25 years. We're very
unhappy about that and we're not going to stand for it."
His group is researching how to identify tumors that demonstrate
aggressive behavior. Already they have found a protein that regulates
metastasis. Soon, they will publish results of their successful
attempts to use proteomics — the study of proteins in a cell
or tissue — to predict cancer recurrence probability.
"We don't view pediatric deaths as statistics," he said. "Every
single child who dies of pediatric cancer is a real catastrophe,
a real tragedy."
Helman also talked frankly about the economics of cancer research
and treatment. For example, he said that in the United States,
about 10,000 cases of adult leukemia occur each year, with about
40 percent (4,000 cases) expressing the FLT3 gene. In contrast,
there are 3,000 pediatric leukemia cases per year, with 15 percent
(450) of those diagnosed with AML. A quarter of those express the
FLT3 mutation, he said, "so you're looking at just about 100 cases — not
much of a monetary incentive" for companies to develop the drug.
Finally, Helman addressed moral and ethical concerns raised by
a burgeoning era of designer therapy. It's fortunate, he said,
that so far, so many aspects of cancer biology have been universal,
their lessons transferable from patient to patient, whether adults
or children. "But," he concluded, "there will be unique features
that are totally specific to a cancer and that's where the industry — and
we as a society — deal with individualized therapy. What
if we find a drug that totally cures just 300 cancers? Who's going
to pay for developing that drug? There are huge ramifications."
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